Patent GB-583815-A (GB)
Title: New pyrimidine compounds
Filed: 1944-05-18
Abstract: Pyrimidine compounds, useful as chemotherapeutic agents, of the general formula <FORM:0583815/IV/1> wherein X and Y represent hydrogen or hydrocarbon radicals or jointly an alkylene chain, R11 represents hydrogen or an alkyl or simply substituted alkyl (e.g. alkoxyalkyl or dialkylaminoalkyl) group, A represents an aliphatic, alicyclic or aliphatic-carbocyclic linking group, which may be substituted (e.g. by hydrocarbon radicals or hydroxy, alkoxy or dialkylaminoalkyl groups), and which, when wholly or partly an aliphatic chain, may be interrupted by oxygen, sulphur or nitrogen atoms, and NRR1 represents a strongly basic amino or substituted amino group (e.g. alkylamino or dialkylamino, or piperidino or other strongly basic nitrogen-containing heterocyclic group), are manufactured by the interaction of a diamine NHR11-A-NRR1 with an appropriate 2-aminopyrimidine bearing the atoms or groups Y and X in the 5- and 6-positions and a halide group, such as a halogen atom or a hydrocarbon radical which is attached by means of an ether or thioether linkage (e.g. an alkoxy, aryloxy or alkylmercapto group), in the 4-position.  Alternatively, such a pyrimidine derivative is reacted with an amino compound of the form NHR11-A1-B, wherein A1 represents either the whole or part of the group A above and B represents a reactive group which is then converted directly or indirectly, by methods involving the step of reaction with ammonia or a compound containing an amino group, into the amino group NRR1 or into a group A11-NRR1 such that A1 and A11 together constitute the group A above.  Thus the group B may be a hydroxy group or a derivative thereof which is, or is readily convertible to, a reactive ester thereof (e.g. a halide), which is then reacted with an amine, an amino-substituted amine or a hydroxy- or mercapto-substituted amine.  Alternatively, when R1 is hydrogen, the diamine is replaced by its acyl derivative NHR11-A-NR-acyl, and the acyl group is subsequently hydrolysed off.  The terminal amino group, when unsubstituted, may be subsequently modified by alkylation, conversion to a heterocyclic group, or reaction with a halogen-substituted amine Hal-A111-NRR1 so as to extend the linking group A to A-NH-A111.  The reactions are effected by heating the reagents together, optionally in the presence of a solvent or diluent.  Either of the reagents may be used in the form of a salt (e.g. hydrochloride or acetate), and, if desired, an acid-binding agent such as sodium hydroxide may be present.  The products form salts with mineral or organic acids such as hydrogen halides and sulphuric, phosphoric, acetic, lactic, tartaric, lower alkanesulphonic (e.g. methanesulphonic), picric, 3 : 5-dinitrobenzoic, methylene bis-2 : 3-hydroxy-naphthoic and methylene bis-salicylic acids.  In examples, pyrimidine derivatives of the general formula given above are made from: 2-amino-4-chloro-5 : 6-dimethylpyrimidine and b -diethyl-or dimethyl-aminoethylamine, g -diethyl-, dimethyl- or di-n-butyl-aminopropylamine, d -diethylaminobutylamine, d  - diethylamino - a  - methylbutylamine, g - n - butylaminopropyl - amine, g -piperidinopropylamine, g -(N-methyl-N - b 1 - diethylaminoethyl) - aminopropylamine, g -(b 1-diethylaminoethoxy)-propylamine, ethylene diamine or b -diethylaminoethylmethylamine; 2-amino-4 - chloro - 5 - ethyl - 6 - methylpyrimidine and d -diethylamino-a -methylbutylamine or b -diethylaminoethylamine; 2-amino-4 - chloro - 6 - methylpyrimidine and b  - diethylaminoethylamine or d -diethylamino-a -methylbutylamine; 2 - amino - 4 - chloro - 5 - benzyl - 6 - methylpyrimidine and b  - diethylaminoethyl - amine, g  - diethylaminopropylamine or d  - di - ethylamino-a -methylbutylamine; 2-amino-4-chloro - 5 : 6 - tri- or tetramethylenepyrimidine and the same three diamines; and from 2 - amino - 4 - chloro - 5 - methylpyrimidine and b -diethylaminoethylamine or g -diethylaminopropylamine.  In a further example, a solution of 2 - amino - 4 - b  - aminoethylamino - 5 : 6 - dimethylpyrimidine and n-butyraldehyde in alcohol is shaken with hydrogen in the presence of a palladium-barium sulphate catalyst to produce 2-amino-4-b -n-butylaminoethylamino-5 : 6-dimethylpyrimidine. Additional starting materials specified are, on the one hand, 2-amino-4-chloropyrimidine and the 4-bromo-, 4-ethoxy-, 4-phenoxy- and 4-methylmercapto-compounds corresponding to this starting material and to those of the examples; and, on the other hand, 3 - diethylamino - 1 : 2 - dimethylpropylamine, 3 - diethylamino - 2 - hydroxypropylamine, 2 - methylaminoethyl - amine, 3 - (b -diethylaminoethylmercapto) - propylamine, 5 - diethylamino - 1 - aminopentane, 2 - pyrrolidinoethylamine, 1 : 3 - bis - diethyl - amino-2-aminopropane, N-ethyl-N-b -diethylaminoethylethylenediamine, 2 - piperidinoethylamine, p-diethylaminoethoxyaniline, p-diethylaminoethylmercaptoaniline, 3 - diethylamino - 2 : 2 - dimethylpropylamine, b  - piperidino - b  - methylethylamine, N-methyl- and N-ethyl-N1-diethylethylenediamine and bis - (b  - diethyl - aminoethyl)-amine.  According to the second Provisional Specification, the substituent Y in the 5-position may be any neutral substituent.  2-Aminopyrimidines containing ether or thioether groups in the 4-position, are obtainable by interaction of the corresponding 4-halogenoderivatives with the appropriate hydroxy or mercapto compounds or alkali metal derivatives thereof. 2-Amino-4-chloro-5-benzyl-6-methylpyrimidine is obtained by refluxing phosphorus pentachloride with the corresponding 4-hydroxy-compound, which may be made by interaction of guanidine hydrochloride with ethyl a -benzylacetoacetate in the presence of sodium ethoxide. 2-Amino-4-chloro-5 : 6-tetramethylenepyrimidine is obtainable by the action of phosphorus oxychloride on the corresponding 4-hydroxy-compound.  2-Amino-4-chloro-5 : 6-trimethylenepyrimidine may be similarly prepared from the corresponding 4-hydroxy-compound obtainable by interaction of guanidine hydrochloride with ethyl cyclopentanone-2-carboxylate in the presence of sodium ethoxide. 2-Amino-4-chloro-5-methylpyrimidine is obtainable similarly from the 4 - hydroxy - compound made by interaction of guanidine hydrochloride with sodium a -formylpropionic ester (obtained from ethyl formate, ethyl propionate and sodium).